A ten-year NIH-funded study has determined that a third of infants with prolonged seizures and fever suffer from either a new or reactivated roseola virus infection. Roseola viruses are the cause of the common childhood rash, but can also cause limbic encephalitis, a condition that frequently progresses to epilepsy. Investigators discovered one of the roseola viruses, human herpesvirus-6B (HHV-6B) in the blood of 32% of 169 infants with prolonged seizures, a condition known as status epilepticus. They found HHV-7 (another roseola virus) in 7.1% of the patients, usually as a co-infection with HHV-6B.

The study strengthens the link between HHV-6B and mesial temporal lobe epilepsy. HHV-6B is the primary cause of limbic encephalitis in transplant patients and half of those cases go on to develop epilepsy within 3-5 years. Furthermore, several studies have found HHV-6B DNA at high levels in the brain tissue of patients with refractory epilepsy. “A clinical trial is urgently needed to determine if repeat seizures and some cases of temporal lobe epilepsy might be prevented using existing antiviral therapy,” said Kristin Loomis, executive director of the HHV-6 Foundation.

These viruses persist in the brain cells and can be activated during periods of immunosuppression or stress. HHV-6 and HHV-7 are spread via the saliva and nearly 100% of the population has been infected by early adulthood.

Do childhood viruses smolder and emerge later as full-blown epilepsy?

“It is possible that these patients harbor latent virus in the brain tissue that reactivates later in response to unknown triggers,” said Leon Epstein, MD, a pediatric neurologist at the Northwestern University Feinberg School of Medicine and Ann & Robert H. Lurie Children’s Hospital of Chicago. Dr. Epstein is the lead author of this new study published in the journal Epilepsia.

While febrile or fever–related seizures occur in 2-5% of infants, most of whom recover with no consequences, less is known about the outcome in children who suffer from the prolonged febrile seizures associated with HHV-6 or HHV-7. These children are still being followed and investigators expect that 30-40% of them will develop epilepsy within five years.

Would some infants with prolonged seizures benefit from antiviral treatment?

Currently infants with seizures are not tested for HHV-6B or HHV-7 and treatment consists of anti-seizure drugs. However, the authors expect clinical trials to be established as soon as more evidence is gathered. Transplant patients suffering with seizures from HHV-6 reactivation are routinely treated with antivirals and antiviral treatment is now common practice for symptomatic infants infected with a closely virus: cytomegalovirus or CMV (HHV-5). Infants who contract CMV from their mothers during pregnancy or shortly following birth can develop seizures and mental retardation as well as permanent losses in both hearing and vision. Antiviral therapy reduces neurological complications and seizures in these infants. The neurologists who conducted the study remain cautious about antiviral therapy. They note that the oral antiviral drug used to treat CMV infections, valganciclovir, can cause reversible neutropenia, a form of anemia; less toxic antivirals such as CMX001 are in the pipeline.

“HHV-6B can cause a strong cytokine response, and there is emerging data that inflammatory mechanisms may be involved in developing epilepsy after an insult such as a prolonged seizure,” explained, Shlomo Shinnar, MD, PhD, of Montefiore Medical Center and Albert Einstein College of Medicine, and principal investigator of the study, “So it is possible that anti-inflammatory treatment could benefit these patients whether or not HHV-6B is the cause of the prolonged seizure. This is an area that needs further research.

HHV-6B reactivation associated with cognitive impairment

Investigators will also be studying the roseola virus subset to determine if they develop cognitive problems in the years following the seizures. “We know that children and adults with temporal lobe epilepsy have cognitive problems. It will be interesting to see whether those who started out with an HHV-6B infection have more cognitive impairment down the road,” said Shinnar.

A study by Danielle Zerr, an infectious disease specialist at Seattle Children’s Hospital and the University of Washington, suggests that Shinnar may be on the right track. She reported last year that patients who reactivate with HHV-6B during a transplant procedure are far more likely to develop cognitive dysfunction or delirium. The declines were especially significant in areas of attention, processing speed, and concentration, as well as cognitive flexibility or the ability to operate with divided attention.

Children who develop seizures in response to these common viruses may harbor genes that cause them to be susceptible. A mutation in the SCN1A gene has been linked to several epilepsy conditions. Variants of another gene, IRF5, have been associated with active HHV-6A infections in multiple sclerosis patients.

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ABOUT THE HHV-6 FOUNDATION

The HHV-6 Foundation in a non-profit entity founded to encourage scientific exchange between investigators and to provide pilot grants for promising scientific and clinical research on the under- appreciated viruses HHV-6A and HHV-6B.

The Foundation sponsors international conferences and supports scientists and clinicians seeking to clarify the role of the two HHV-6 viruses in disease. Since HHV-6A and HHV-6B can smolder in the brain and other organs without circulating in the peripheral blood or plasma, identifying chronic infection is a challenge.